ClinVar Genomic variation as it relates to human health
NM_002693.3(POLG):c.2665G>A (p.Ala889Thr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(4); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002693.3(POLG):c.2665G>A (p.Ala889Thr)
Variation ID: 448104 Accession: VCV000448104.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q26.1 15: 89321194 (GRCh38) [ NCBI UCSC ] 15: 89864425 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 19, 2017 May 1, 2024 Jan 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002693.3:c.2665G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002684.1:p.Ala889Thr missense NM_001126131.2:c.2665G>A NP_001119603.1:p.Ala889Thr missense NC_000015.10:g.89321194C>T NC_000015.9:g.89864425C>T NG_008218.2:g.18602G>A LRG_765:g.18602G>A LRG_765t1:c.2665G>A LRG_765p1:p.Ala889Thr - Protein change
- A889T
- Other names
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- Canonical SPDI
- NC_000015.10:89321193:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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POLG | - | - |
GRCh38 GRCh37 |
1 | 2962 | |
POLGARF | - | - | GRCh38 | - | 2918 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 22, 2023 | RCV000518474.25 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 4, 2024 | RCV000695266.9 | |
not provided (1) |
no classification provided
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- | RCV000844909.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 10, 2020 | RCV002438244.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Mar 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000614717.4
First in ClinVar: Dec 19, 2017 Last updated: Sep 19, 2021 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to impair polymerase activity (PMID: 17980715). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. (less)
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Pathogenic
(May 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001769542.2
First in ClinVar: Aug 07, 2021 Last updated: Oct 05, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33486010, 17980715, 19010300, 12975295, 29474836, 15800909, 33791913, 25462018, 32347949, 20883824, 17950645, 24099403, 20185557, 22470557, 35114397) (less)
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Likely pathogenic
(Sep 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004205869.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000823754.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 889 of the POLG protein (p.Ala889Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 889 of the POLG protein (p.Ala889Thr). This variant is present in population databases (rs763393580, gnomAD 0.07%). This missense change has been observed in individuals with autosomal recessive progressive external ophthalmoplegia (PEO) (PMID: 12975295, 24099403, 29474836). This variant has also been reported as occurring in cis with a polymorphism variant (p.Glu1143Gly) in a family with 2 brothers affected with PEO and neurological features; however, additional family members with these variants including the mother and 2 maternal uncles did not have PEO (PMID: 15800909). ClinVar contains an entry for this variant (Variation ID: 448104). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects POLG function (PMID: 17980715, 25462018). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334803.19
First in ClinVar: Jun 08, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Mar 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002744841.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.A889T variant (also known as c.2665G>A), located in coding exon 16 of the POLG gene, results from a G to A substitution at nucleotide … (more)
The p.A889T variant (also known as c.2665G>A), located in coding exon 16 of the POLG gene, results from a G to A substitution at nucleotide position 2665. The alanine at codon 889 is replaced by threonine, an amino acid with similar properties. This variant was detected in a homozygous sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO) case, as well as in several unaffected heterozygous family members (Bandettini di Poggio M et al. BMC Med. Genet., 2013 Oct;14:105). This variant has also been reported in individuals with progressive external ophthalmoplegia (PEO) and myoclonic epilepsy myopathy sensory ataxia (MEMSA), some of whom had additional POLG variants detected; however, information about phase (cis or trans) was not provided (Filosto M et al. Arch. Neurol., 2003 Sep;60:1279-84; Hisama FM et al. Am. J. Med. Genet. A, 2005 Jun;135:217-9; Boddaert N et al. Mol. Genet. Metab., 2008 Jan;93:85-8). Functional studies in yeast models suggested some impact; however clinical relevance in humans has not been determined (Baruffini E et al. Biochim. Biophys. Acta, 2007 Dec;1772:1225-35). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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POLG-Related Disorders
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000986716.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Comment:
Variant interpretted as Likely pathogenic and reported on 06/02/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpretted as Likely pathogenic and reported on 06/02/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormality of eye movement (present) , Abnormality iris morphology (present) , Cognitive impairment (present) , Abnormality of coordination (present) , EEG abnormality (present) , Generalized … (more)
Abnormality of eye movement (present) , Abnormality iris morphology (present) , Cognitive impairment (present) , Abnormality of coordination (present) , EEG abnormality (present) , Generalized hypotonia (present) , Seizures (present) , Abnormality of facial musculature (present) , Abnormality of muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Feeding difficulties (present) (less)
Age: 0-9 years
Sex: male
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-06-02
Testing laboratory interpretation: Likely pathogenic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Quantitative neuroimaging biomarkers in a series of 20 adult patients with POLG mutations. | Masingue M | Mitochondrion | 2019 | PMID: 29474836 |
Polymorphisms in DNA polymerase γ affect the mtDNA stability and the NRTI-induced mitochondrial toxicity in Saccharomyces cerevisiae. | Baruffini E | Mitochondrion | 2015 | PMID: 25462018 |
Dopamine-agonist responsive Parkinsonism in a patient with the SANDO syndrome caused by POLG mutation. | Bandettini di Poggio M | BMC medical genetics | 2013 | PMID: 24099403 |
Overexpression of DNA polymerase zeta reduces the mitochondrial mutability caused by pathological mutations in DNA polymerase gamma in yeast. | Baruffini E | PloS one | 2012 | PMID: 22470557 |
Predicting the contribution of novel POLG mutations to human disease through analysis in yeast model. | Baruffini E | Mitochondrion | 2011 | PMID: 20883824 |
mip1 containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae. | Stumpf JD | Human molecular genetics | 2010 | PMID: 20185557 |
1H MRS spectroscopy evidence of cerebellar high lactate in mitochondrial respiratory chain deficiency. | Boddaert N | Molecular genetics and metabolism | 2008 | PMID: 17950645 |
Mitochondrial DNA defects in Saccharomyces cerevisiae caused by functional interactions between DNA polymerase gamma mutations associated with disease in human. | Baruffini E | Biochimica et biophysica acta | 2007 | PMID: 17980715 |
Molecular diagnosis of Alpers syndrome. | Nguyen KV | Journal of hepatology | 2006 | PMID: 16545482 |
Progressive external ophthalmoplegia: a new family with tremor and peripheral neuropathy. | Hisama FM | American journal of medical genetics. Part A | 2005 | PMID: 15800909 |
Clinical and genetic heterogeneity in progressive external ophthalmoplegia due to mutations in polymerase gamma. | Filosto M | Archives of neurology | 2003 | PMID: 12975295 |
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Text-mined citations for rs763393580 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.